The Weissman lab has discovered that cancer cells evade clearance by the immune system through increased expression of CD47, a surface molecule that binds to the inhibitory receptor called signal-regulatory protein alpha (SIRP?) on phagocytic cells, thereby inhibiting phagocytosis. I have found that persistently infected cells in a variety of infectious diseases also upregulate CD47 expression. Furthermore, I discovered that T cells upregulate SIRP? in response to prolonged activation, and together with collaborators have confirmed this in two distinct chronic viral infections. Most strikingly, T cell that upregulate SIRP? also have high expression levels of programmed cell death 1 (PD-1), a mediator of exhaustion. I hypothesize that the CD47-SIRP? axis is an immunomodulatory axis, whereby overexpression of CD47 in infected cells triggers SIRP? mediated blockade of both innate and adaptive immune clearance. This makes the CD47- SIRP? interaction an important target for novel immunotherapies. To this end we have developed multiple reagents to block this interaction, which we will test in vivo in mouse models of chronic infection as well as with human in vitro and patient ex vivo models. I will expand my exploration of SIRP? as a novel marker of T cell exhaustion to determine whether SIRP? is upregulated on exhausted human T cells from HIV infected individuals. I will also investigate the function of SIRP? on T cells. Concurrently w will test whether therapeutic blockade of SIRP? signaling, either alone or in combination with additional inhibitors of T cell exhaustion, can restore functionality of exhausted T cells or lead o clearance of the persistent infection. If successful the proposed experiments will demonstrate the preclinical efficacy of CD47 blockade in infectious diseases, identify a novel marker of T cell exhaustion, and specifically test if targeting the CD47- SIRP? axis can restore functionality to exhausted T cells.